Malignant melanoma is the most invasive and deadly form of skin cancer with no effective therapy to treat advanced disease, leading to poor survival rates. Targeted combinatorial therapeutics is needed that inhibit proteins or pathways causing melanoma. Regrettably, relatively few targets have been identified or no therapeutic agents are available to inhibit them. Recently, we identified elevated Akt3 activity occurring in ~70% of sporadic melanomas compared to normal cells. Functionally, active Akt3 reduces responsiveness of melanomas to agents that would normally kill via apoptosis, thereby promoting tumorigenesis and development of chemoresistance. Unfortunately, no agents are available to inhibit this important pathway in melanomas. Furthermore, it is unknown whether targeting Akt3 signaling would be therapeutically sufficient or whether a combinatorial approach targeting other melanoma causing proteins, such as V600E B-Raf, would be necessary for an effective therapeutic. Based on these important unanswered questions, the central hypothesis for this proposal is that targeting Akt3 signaling alone or in combination with V600E B-Raf inhibition would be an effective targeted approach for inhibiting melanoma. The hypothesis will be tested by: (1) characterizing the utility of novel synthetic isothiocyanate and isoselenocyanate derivatives that inhibit Akt3 signaling to reduce melanoma tumorigenesis and metastasis; and (2) determining the therapeutic potential of a combinatorial approach targeting Akt3 and V600E B-Raf signaling in melanomas. We are prepared to undertake the proposed research, having demonstrated that the Akt3 and V600EB-Raf pathways are key therapeutic targets in melanoma and development of novel synthetic compounds derived from chemopreventive isothiocyanates to inhibit Akt3 signaling. Accomplishing these goals would be highly significant, providing novel insight into the therapeutic implications of targeting a major signaling pathway in melanoma, and provide solid rationale for initiating clinical trials in melanoma patients targeting Akt3 signaling. For melanoma patients, these discoveries could ultimately lead to development of improved therapeutics that would increase length and quality of life for individuals suffering from this disease. Over the long-term, discovery of therapeutics and effective approaches to inhibit the Akt3 signaling pathway are predicted to have a significantly positive impact on the currently poor prognosis faced by advanced-stage melanoma patients. Specifically these agents would contribute to the availability of more effective therapies, which would increase the length and quality of life for melanoma patients. Therefore, the positive impact of this study on the melanoma therapeutics field will be significant.